The causal association between inappropriate protein kinase activation and cancer is well established, and several protein kinase oncogenes have been identified (Broach and Levine, Current Opin. Genet. Dev., 25:6464-6474, 1997; Hanahan and Weinberg, Cell, 100:57-70, 2000). On the other hand, the role of protein phosphatases in cancer development has been under investigated and is less well understood.
The PP2A family is a diverse group of ubiquitously expressed serine-threonine phosphatases that have been causally linked to cancer development. Somatic mutations of the PP2A structural Aβ subunit have been observed in 8-15% of colon cancers, 15% of lung cancers, 13% of breast cancers, and 6% of tumor cell lines (Calin et al., Oncogene, 19:1191-1195, 2000; Ruediger et al., Oncogene, 20:1892-1899, 2001; Takagi et al., Gut, 47:268-271, 2000; Tamaki et al., Oncol. Rep., 11:655-659, 2004; Wang et al., Science, 282:284-287, 1998). Furthermore, deletions of the PP2A Aβ gene and reduced expression of the PP2A Aβ subunit has been reported in 16 of 32 cancer cell lines derived from human lung, colon, breast, and cervical carcinomas (Baysal et al., Eur. J. Hum. Genet., 9:121-129, 2001; Zhou et al., Biochem. J., 369:387-398, 2003). Despite recent advances in the search for cancer therapies, there still remains no truly effective treatment. While the examples above point to a clear association between the PP2A family and cancer, the molecular mechanism involved have not been characterized and its potential for cancer therapy not investigated.
RalA is a multifunctional protein, regulating membrane transport, apoptosis, transcription, cell migration and cell proliferation (Camionis, J. H., and White, M. A., Trends Cell Biol., 115:327-332, 2005; Feig, L. A., Trends Cell Biol., 13:419-425, 2003). RalA activation results in activation of several signaling pathways, including the activation of phospholipase D1 and Src kinase (Goi et al., Embo. J., 19:623-630, 2000; Jiang et al., Nature, 378:409-412, 1995), vesicle transport (Moskalenko et al., Nat. Cell. Biol., 4:66-72, 2002), filopodia formation (Ohta et al., Proc. Natl. Acad. Sci., 96:2122-2128, 1999), epidermal growth factor-induced cell motility (Gildea et al., Cancer Res., 62:982-985, 2002) and AI growth (Chien, Y., and White, M., A., EMBO Rep., 4:800-806, 2003; Lim et al., Cancer Cell., 7:533-545, 2005; Panner et al., Mol. Cell. Biol., 2006). The activation of known RalA effector proteins such as RalBP1 or the exocyst has not previously been directly linked to tumorigenesis. However, other signaling molecules regulated by RalA, such as phospholipase D1, Src, JNK, NF-κB and cyclin D, may contribute to cancer progression (Feig, L. A., Trends Cell Biol., 13:419-425, 2003; Lim et al., Cancer Cell., 7:533-545, 2005).